Diminished Neurogenic Femoral Artery Vasoconstrictor Response in a Zucker Obese Rat Model: Differential Regulation of NOS and COX Derivatives

Abstract

ObjectivePeripheral arterial disease is one of the macrovascular complications of type 2 diabetes mellitus. This study addresses femoral artery regulation in a prediabetic model of obese Zucker rats (OZR) by examining cross-talk between endothelial and neural factors.Methods and ResultsArterial preparations from lean (LZR) and OZR were subjected to electrical field stimulation (EFS) on basal tone. Nitric oxide synthase (NOS) and cyclooxygenase (COX) isoform expression patterns were determined by immunohistochemical labelling and Western blotting. Results indicate significantly reduced noradrenergic contractions in preparations from OZR compared with those of LZR. Functional inhibition of endothelial NOS (eNOS) indicated a predominant role of this isoform in LZR and its modified activity in OZR. Neural (nNOS) and inducible NOS (iNOS) were activated and their expression was higher in femoral arteries from OZR. Neurotransmission modulated by large-conductance Ca2+-activated (BKCa) or voltage-dependent (KV) K+ channels did not seem compromised in the obese animals. Endothelial COX-1 and COX-2 were expressed in LZR and an additional adventitial location of COX-2 was also observed in OZR, explaining the higher COX-2 protein levels detected in this group. Prostanoids derived from both isoforms helped maintain vasoconstriction in LZR while in OZR only COX-2 was active. Superoxide anion inhibition reduced contractions in endothelium-intact arteries from OZR.ConclusionsEndothelial dysfunction led to reduced neurogenic vasoconstriction in femoral arteries from OZR. In a setting of obesity, NO-dependent nNOS and iNOS dilation activity could be an alternative mechanism to offset COX-2- and reactive oxygen species-mediated vasoconstriction, along with impaired endothelial NO relaxation.

Trimethylamine-<i>N</i>-oxide Specifically Impairs Endothelium-Derived Hyperpolarizing Factor-Type Relaxation in Rat Femoral Artery

“…26) Endothelial dysfunction is a precursor for the development of atherosclerosis, and is seen in femoral arteries in diseases associated with peripheral arterial disease, including hypertension and diabetes. 29,30) Therefore, our findings suggest that TMAO is a causative factor in the development of peripheral arterial disease. To get a comprehensive understanding of the effects of TMAO on vascular function, future studies are required on the relationship among exposed concentration, exposed time, vessel types including resistance-size arteries, vascular functions, and TMAO.…”

“…Second, previous studies have reported that the circulating levels of TMAO are approximately between 10 −6 and 10 −4 mol/L range in vivo for animal models and humans. 10,[26][27][28] Although we used a higher concentration of TMAO compared with plasma levels, the local level of TMAO may transiently reach higher concentrations. Elevated circulating TMAO levels may be an important prognostic marker in patients with a peripheral arterial disease.…”

Effects of an Antimutagenic 1,4‐Dihydropyridine AV‐153 on Expression of Nitric Oxide Synthases and DNA Repair‐related Enzymes and Genes in Kidneys of Rats with a Streptozotocin Model of Diabetes Mellitus

“…The observed increase in iNOS in diabetic animals was quite anticipated, as numerous researchers report similar facts. Increase in iNOS expression precedes the cardiomyocyte death in diabetic hearts [16]; the enzyme is up-regulated in the blood vessels of animals genetically predisposed to DM [27]. iNOS expression is triggered by the nuclear factor-kappa B (NF-jB); the latter is up-regulated by hyperglycaemia-induced oxidative stress and after protein nitration [28].…”

Constrictor prostanoids and uridine adenosine tetraphosphate: vascular mediators and therapeutic targets in hypertension and diabetes

“…In diabetic animal models, COX‐2‐derived prostanoids have been suggested to induce abnormal vasoconstrictor responses or to account for the development of endothelium‐derived vasoconstrictor activity (Quilley and Chen, ; Bagi et al ., ; Guo et al ., ; Nacci et al ., ; Lopez‐Lopez et al ., ; Ramos‐Alves et al ., 2012a,b; Vessieres et al ., ). Indeed, COX‐2 expression and activity are increased in diabetic arteries (Bagi et al ., ; Sanchez et al ., ; Kassan et al ., ; Martinez et al ., ). Moreover, at the cellular level, high glucose, which is a characteristic of diabetes (De Vriese et al ., ; Rask‐Madsen and King, 2007; 2013; Forbes and Cooper, ), increases COX‐2 expression and activity in ECs (Cosentino et al ., ; Sheu et al ., ).…”